Bilirubin reduces mortality in sepsis models by inhibiting NOX2-mediated formation of neutrophil extracellular traps.

OBJECTIVES: Sepsis is a life-threatening condition driven by a dysregulated immune response to infection, yet therapeutic options beyond antibiotics and vasopressors remain limited. Neutrophil extracellular traps (NETs) contribute significantly to sepsis-induced tissue injury, and NETosis inhibition has emerged as a potential therapeutic strategy. We hypothesized that the endogenous metabolite bilirubin mitigates inflammation in sepsis by inhibiting NETosis through targeting NOX2. METHODS: . Mechanistic studies included ROS measurements, NOX2 loop C mutational analysis, and inhibition of endocytosis and autophagy to examine how bilirubin modulates NOX2 stability. RESULTS: Bilirubin improved survival and reduced NET biomarkers in both models. It inhibited NETosis in human neutrophils by suppressing ROS-dependent NETosis and promoting the internalization and degradation of NOX2 via endocytosis and autophagy. DISCUSSION: These findings identify bilirubin as an endogenous inhibitor of NETosis. By targeting NOX2 and suppressing NETosis, bilirubin may represent a promising therapeutic candidate for sepsis management.